Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers

Tetrahydrobiopterin (BH₄) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH₄, is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH₄ as a pharmacological agent for diseases associated with BH₄-deficient conditions. We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5-80 mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean C_max 0.58-2.92 ng/mL) and BH₄ (mean C_max 57-312 ng/mL). Maximum plasma concentrations were achieved in about 1-2 h (sepiapterin) or about 4 h (BH₄) after CNSA-001 oral intake. Increases in plasma BH₄ were substantially larger in absolute terms and on a dose-for-dose basis following treatment with CNSA-001 vs. sapropterin dihydrochloride, a synthetic form of BH₄. The pharmacokinetics of plasma sepiapterin and BH₄ were similar before and after seven days of repeat daily dosing with CNSA-001 at 5, 20 or 60 mg/kg indicating little or no drug accumulation. Oral administration of CNSA-001 resulted in higher concentrations of sepiapterin in fasted vs. fed subjects, but overall BH₄ plasma exposure following CNSA-001 intake increased by 1.7-1.8-fold in fed subjects. CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH₄ in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH₄ deficiencies and other diseases associated with deficient BH₄ metabolism.